The present invention relates to indanes and benzopyrans and analogues thereof which are potassium channel inhibitors and thus are useful as antiarrhythmic agents.
In accordance with the present invention, novel indanes and benzopyrans and analogues thereof are provided which are potassium channel inhibitors and have the structure 
including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof, wherein
A, B and D are independently selected from CH or N;
X1 is 
xe2x80x83(where n is 1, 2 or 3),
O, NR5, S, SO, SO2 
xe2x80x83or 
xe2x80x83wherein the hetero atom in each of the above groups is linked to the aromatic ring; (where R3 and R4 are independently H, alkyl, arylalkyl or cycloalkyl, or R3 and R4 can be taken together with the carbon to which they are attached to form a 5 to 8 carbon containing ring; and R5 is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
R is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, or cycloalkylalkyl;
R1 is alkyl, arylalkyl, aryl, alkenyl, heterocyclo, heterocycloalkyl, 
xe2x80x83(where R5a can be any of the R5 groups), cycloalkyl, cycloalkylalkyl or 
xe2x80x83(where R6 and R7 are independently selected from H, aryl, alkyl, arylalkyl or cycloalkyl, or R6 and R7 can be taken together with the nitrogen atom to which they are attached to form a 5 to 8 membered ring); or R and R1 can be taken together with the xe2x80x94Nxe2x80x94Sxe2x80x94 atoms to form a 5- to 8-membered ring;
X2 is a single bond, 
xe2x80x83or xe2x80x94Oxe2x80x94 (where R8 is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
R2 is H, alkyl, arylalkyl, 
xe2x80x83or 
xe2x80x83(where R10 and R11 are independently selected from H, alkyl, arylalkyl, or cycloalkyl, or R10 and R11 can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring); and
Q is 
xe2x80x83or R2-heterocycle (where R12 is alkyl, arylalkyl, aryl, 
xe2x80x83heterocycle, heterocycloalkyl, 
xe2x80x83(where R14 can be any of the R8 groups), alkoxy, CF3, aryloxy, arylalkoxy, cycloalkyl or cycloalkylalkyl, and where R15 and R16 are independently selected from H, alkyl, arylalkyl, aryl, heterocyclo, cycloalkyl, amino, aminoalkyl, or heterocycloalkyl, or R15 and R16 can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring which may optionally contain an additional nitrogen atom in the ring and/or an amino group or an aminoalkyl group attached to the ring); and
R13 is 
xe2x80x83(wherein this moiety is as defined with respect to R12).
Preferred com;pounds of formula I of the invention can have the following structural formulae: 
Preferred are compounds of formula I wherein Q is 
xe2x80x83or 
xe2x80x83wherein heterocycle is a monocyclic ring (cycloheteroalkyl ring or heteroaryl ring) containing 5 or 6 ring members which include one or two nitrogen atoms in the ring and/or one oxygen atom in the ring.
Also preferred are compounds of formula I where
R is H;
R1 is aryl or alkyl;
X2 is O or a single bond;
R2 is H;
X1 is 
xe2x80x83or 
xe2x80x83where R3 and R4 are each H and/or alkyl;
A and B are each CH;
D is N or CH; and
Q is 
xe2x80x83or 
xe2x80x83where R15 and R16 are H, aryl, aralkyl or aminoalkyl.
Still more preferred are compounds of formula I where
R is H;
R1 is aryl;
X2 is O or a single bond;
R2 is H;
X1 is 
xe2x80x83or 
X1 is
A and B are each CH;
D is N or CH; and
Q is 
xe2x80x83or 
In addition, in accordance with the present invention, a method for preventing, inhibiting or treating cardiac arrhythmia, including atrial arrhythmia, is provided, wherein a compound of formula I is administered in a therapeutically effective amount which inhibits the IKur potassium channel.
The formula I compound employed in the above method has the structure 
including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof, wherein
A, B and D are independently selected from CH or N;
X1 is 
xe2x80x83(where n is 1, 2 or 3),
O, NR5, S, SO, SO2, 
xe2x80x83or 
xe2x80x83wherein the heteroatom in each of the above groups is linked to the aromatic ring;
(where R3 and R4 are independently H, alkyl, arylalkyl or cycloalkyl, or R3 and R4 can be taken together with the carbon to which they are attached to form a 5 to 8 carbon containing ring; and R5 is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
R is H, alkyl, alkenyl, aryl, arylalkyl, heterocycloalkyl, cycloalkyl, or cycloalkylalkyl;
R1 is alkyl, arylalkyl, aryl, alkenyl, heterocyclo, heterocycloalkyl, 
xe2x80x83(where R5a can be any of the R5 groups), cycloalkyl, cycloalkylalkyl or 
xe2x80x83(where R6 and R7 are independently selected from H, aryl, alkyl, arylalkyl or cycloalkyl, or R6 and R7 can be taken together with the nitrogen atom to which they are attached to form a 5 to 8 membered ring); or R and R1 can be taken together with the xe2x80x94Nxe2x80x94Sxe2x80x94 atoms to form a 5- to 8-membered ring;
X2 is a bond, 
xe2x80x83or xe2x80x94Oxe2x80x94 (where R8 is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
R2 is H, alkyl, arylalkyl, 
xe2x80x83or 
xe2x80x83(where R10 and R11 are independently selected from H, alkyl, arylalkyl or cycloalkyl, or R10 and R11 can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring); and
Q is 
xe2x80x83or R12-heterocycle (where R12 is alkyl, arylalkyl, aryl, 
xe2x80x83heterocycle, heterocycloalkyl, 
xe2x80x83where R14 can be any of the R8 groups), alkoxy, aryloxy, arylalkoxy, cycloalkyl or cycloalkylalkyl, and where R15 and R16 are independently selected from H, alkyl, arylalkyl, heterocyclo, cycloalkyl or heterocycloalkyl, or R15 and R16 can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring (which may optionally contain an additional nitrogen in the ring and/or an amino group or an aminoalkyl group attached to the ring); and
R13 is 
xe2x80x83(wherein this moiety is as defined with respect to R12).
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
Unless otherwise indicated, the term xe2x80x9clower alkylxe2x80x9d, xe2x80x9calkylxe2x80x9d or xe2x80x9calkxe2x80x9d as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons, containing 1 to 40 carbons, preferably 1 to 20 carbons, more preferably 1 to 12 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various additional branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents which may be halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonylamino, acyl, nitro, cyano,thiol, alkylthio or any of the alkyl or aryl substituents set out herein.
Unless otherwise indicated, the term xe2x80x9ccycloalkylxe2x80x9d as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 4 to 12 carbons, forming the ring and which may be fused to one aromatic ring as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl, 
any of which groups may be optionally substituted with 1 to 4 substituents which may be any of the alkyl or aryl substituents set out herein.
The term xe2x80x9ccycloalkenylxe2x80x9d as employed herein alone or as part of another group refers to cyclic hydrocarbons containing 5 to 20 carbons, preferably 6 to 12 carbons and 1 or 2 double bonds. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclohexadienyl, and cycloheptadienyl, which may be optionally substituted as defined for cycloalkyl.
The term xe2x80x9carylxe2x80x9d as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1-naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings) and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, haloalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, trifluoromethoxy, alkynyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, substituted amino wherein the amino includes 1 or 2 substituents (which are alkyl, aryl or any of the other aryl compounds mentioned in the definitions), thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino or arylsulfonaminocarbonyl.
The term xe2x80x9caralkylxe2x80x9d, xe2x80x9caryl-alkylxe2x80x9d or xe2x80x9caryllower alkylxe2x80x9d as used herein alone or as part of another group refers to alkyl groups as discussed above having an aryl substituent, such as benzyl or phenethyl, or naphthylpropyl, or an aryl as defined above.
The term xe2x80x9clower alkoxyxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d or xe2x80x9caralkoxyxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
The term xe2x80x9caminoxe2x80x9d as employed herein alone or as part of another group may optionally be independently substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with a carboxylic acid or any of the alkyl or aryl substituents set out above. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl, 4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl, 1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
The term xe2x80x9clower alkylthioxe2x80x9d, alkylthioxe2x80x9d, xe2x80x9carylthioxe2x80x9d or xe2x80x9caralkylthioxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to a sulfur atom.
The term xe2x80x9clower alkylaminoxe2x80x9d, xe2x80x9calkylaminoxe2x80x9d, xe2x80x9carylaminoxe2x80x9d, or xe2x80x9carylalkylaminoxe2x80x9d as employed herein alone or as part of another group includes any of the above alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
The term xe2x80x9cacylxe2x80x9d as employed herein by itself or part of another group, as defined herein, refers to an organic radical linked to a carbonyl 
group; examples of acyl groups include any of the R1 groups attached to a carbonyl, such as alkanoyl, alkenoyl, aroyl, aralkanoyl, heteroaroyl, cycloalkanoyl, cycloheteroalkanoyl and the like.
The term xe2x80x9calkanoylxe2x80x9d as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
Unless otherwise indicated, the term xe2x80x9clower alkenylxe2x80x9d or xe2x80x9calkenylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 3 to 12 carbons, and more preferably 1 to 8 carbons in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido, arylcarbonyl-amino, acyl, nitro, cyano, thiol, alkylthio or any of the alkyl or aryl substituents set out herein.
Unless otherwise indicated, the term xe2x80x9clower alkynylxe2x80x9d or xe2x80x9calkynylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 20 carbons, preferably 2 to 12 carbons and more preferably 2 to 8 carbons in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like, and which may be optionally substituted with 1 to 4 substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl, cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino, nitro, cyano, thiol, and/or alkylthio, or any of the alkyl or aryl substituents set out herein.
Where alkyl groups as defined above have single bonds for attachment to other groups at two different carbon atoms, they are termed xe2x80x9calkylenexe2x80x9d groups and may optionally be substituted as defined above for xe2x80x9calkylxe2x80x9d.
Where alkenyl groups as defined above and alkynyl groups as defined above, respectively, have single bonds for attachment at two different carbon atoms, they are termed xe2x80x9calkenylene groupsxe2x80x9d and xe2x80x9calkynylene groupsxe2x80x9d, respectively, and may optionally be substituted as defined above for xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d.
Suitable alkylene, alkenylene or alkynylene groups (CH2)p (where p is 1 to 8, preferably 1 to 5) (which may include alkylene, alkenylene or alkynylene groups) as defined herein, may optionally include 1, 2, or 3 substituents which include any of the alkyl or aryl substituents set out herein.
Examples of alkylene, alkenylene and alkynylene include 
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or fluorine being preferred.
The term xe2x80x9cmetal ionxe2x80x9d refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
The term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocycloxe2x80x9d as used herein alone or as part of another group refers to a xe2x80x9ccycloheteroalkylxe2x80x9d group or a xe2x80x9cheteroarylxe2x80x9d group as defined hereinafter.
The term xe2x80x9cheterocycloalkylxe2x80x9d as used herein alone or as part of another group refers to a heterocycle linked through a carbon to an alkyl group.
The term xe2x80x9ccycloheteroalkylxe2x80x9d as used herein alone or as part of another group refers to a 5-, 6- or 7-membered saturated or partially unsaturated ring which includes 1 to 2 hetero atoms such as nitrogen, oxygen and/or sulfur, linked through a carbon atom or a heteroatom, where possible, optionally via the linker (CH2)p (which is defined above), such as 
and the like. The above groups may include 1 to 4 substituents such as alkyl, halo, oxo and/or any of the alkyl or aryl substituents set out herein. In addition, any of the above rings can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring.
The term xe2x80x9cheteroarylxe2x80x9d as used herein alone or as part of another group refers to a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such. as nitrogen, oxygen or sulfur, and such rings fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring (e.g. benzothiophenyl, indolyl), and includes possible N-oxides. The heteroaryl group may optionally include 1 to 4 substituents such as any of the alkyl or aryl substituents set out above. Examples of heteroaryl groups include the following: 
and the like.
The term xe2x80x9ccycloheteroalkylalkylxe2x80x9d as used herein alone or as part of another gorup refers to cycloheteroalkyl groups as defined above linked through a C atom or heteroatom to a (CH2)p chain.
The term xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheteroarylalkenylxe2x80x9d as used herein alone or as part of another group refers to a heteroaryl group as defined above linked through a C atom or heteroatom to a xe2x80x94(CH2)pxe2x80x94 chain, alkylene or alkenylene as defined above.
The term xe2x80x9cpolyhaloalkylxe2x80x9d as used herein refers to an xe2x80x9calkylxe2x80x9d group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2, CF3 or CF3CF2CH2.
The term xe2x80x9cpolyhaloalkyloxyxe2x80x9d as used herein refers to an xe2x80x9calkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF3CH2O, CF3O or CF3CF2CH2O.
The compounds of formula I can be present as salts, in particular pharmaceutically acceptable salts. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4)-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or p-toluene-sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl-propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.
A preferred salt of the compounds of formula I is the monohydrochloride salt.
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substituents. Consequently, compounds of formula I can exist in enantiomeric or diastereomeric forms or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.
It should be understood that the present invention includes prodrug forms of the compounds of formula I such as alkylesters of acids or any of the prodrugs disclosed in xe2x80x9cProdrugsxe2x80x9d, D. G. Waller, C. F. George, Br. J. Clin. Pharmac. (1989), 28, 497-507; xe2x80x9cProdrugs for the improvement of drug absorption via different routes of administrationxe2x80x9d, L. P. Balant, E. Doelker, P. Burt, Eur. J. Drug Metab. Pharmacokinet. (1990), 15, 143-153; xe2x80x9cProdrugs as a means to improve the delivery of peptide drugsxe2x80x9d, H. Bundgaard, Advanced Drug Delivery Reviews (1992), 8, 1-38; xe2x80x9cNovel chemical approaches in prodrug designxe2x80x9d(1991), Drugs of the Future, 16, 443-458; and in U.S. application Ser. No. 08/641,718, filed May 2, 1996, and in U.S. Pat. No. 5,561,146 which are incorporated herein by reference.
The compounds of the instant invention may, for example, be in the free or hydrate form, and may be obtained by methods exemplified by the following descriptions.
The compounds of formula I may be prepared by the exemplary processes described in the following reaction schemes. Exemplary reagents and procedures for these reactions appear hereinafter and in the working Examples.
Compounds of formula I of the invention can be prepared by using the sequence of steps outlined in General Schemes 1 to 8 set out below. 
Referring to General Scheme 1, amide compounds of the invention of formula IA may be prepared starting with nitrile II which is made to undergo a sulfonylation by reacting II with a sulfonylating agent III (employing a molar ratio of III:II within the range from about 1:1 to about 10:1) in the presence of a base such as triethylamine or diisopropylethylamine in an inert organic solvent such as acetonitrile and/or dichloromethane, to form sulfonylated compound IV.
Compound IV is then subjected to nitrile hydrolysis by treating an aqueous solution of IV with sodium peroxide and then with strong acid such as hydrochloric acid, to form the acid V.
Acid V is treated with amine VI (employing a molar of VI:V within the range from about 1:1 to about 10:1) and a dehydrating agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide with 4-dimethylaminopyridine in the presence of an inert solvent such as acetonitrile and/or dimethylformamide, to form amide compounds of the invention IA.
The starting nitrile II in General Scheme 1 may be prepared as described in K. Atwal et al, J. Med. Chem. (1993) 36, 3971-3974 and references cited therein. 
Referring to General Scheme 2, compounds of the invention of formula IB may be prepared from acid V employing methods known in the literature and described in xe2x80x9cComprehensive Heterocyclic Chemistryxe2x80x9d, A. Katritsky et al, Pergamon, Elsevier Science, Inc., (1996).
Where F is oxygen and E and G are nitrogen, compound IB may be prepared by reaction of the acid V with a hydroxyamidine in the presence of a dehydrating agent such as (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and a tertiary amine such as triethylamine in an inert organic solvent such as dichloromethane. The resulting acylhydroxyamidine can be treated with a base such as potassium, sodium or cesium carbonate in an inert organic solvent such as tetrahydrofuran to provide compound IB. 
Referring to General Scheme 3, compounds of the invention of formula IC where either R15 or R16 is aryl may be prepared starting with compound X which is made to undergo sulfonylation by reacting nitro compound X with sulfonylating agent III (employing a molar ratio of III:X within the range from about 1:1 to about 10:1) in the presence of a base such as triethylamine and an inert organic solvent such as dichloromethane to form sulfonylated compound XI.
Compound XI is reduced, for example, by reacting XI with KBH4 in the presence of CuCl to form aniline XII. Aniline XII is then subjected to cyanoguanidine formation by reacting XII with an N-cyanothiourea sodium salt XIII (employing a molar ratio of XIII:XII within the range from about 1:1 to about 5:1), in the presence of a carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and an inert organic solvent such as anhydrous dimethylformamide, dichloromethane or acetonitrile to form cyanoguanidine of the invention IC.
The starting nitro compound X may be prepared following procedures as described in WO9804521.
The sodium salt of a cyanothiourea XIII may be prepared from the corresponding isothiocyanate and cyanamide as described in Atwal, K. S.; Ahmed, S. Z., O""Reilly, B. O. Tetrahedron Letters (1989) 30, 7313. 
Referring to General Scheme 4, compounds of the invention of formula ID where R15 and R16 are alkyl may be prepared starting with aniline compound XII which is reacted with diphenyl cyanocarbonimidate XI V (employing a molar ratio of XIV:XII within the range from about 1:1 to about 5:1) in an inert organic solvent such as acetonitrile under reflux conditions to form cyanoimidate XV.
Cyanoimidate XV is then reacted with amine XVI (employing a molar ratio of XVI:XV within the range from about 1:1 to about 5:1) in the presence of inert organic solvents such as isopropanol and dimethylsulfoxide to form cyanoguanidine compound of the invention ID. 
Referring to General Scheme 5, compounds of the invention of.the formula IE may be prepared by starting with nitrile II which is made to undergo nitrile hydrolysis with concentrated aqueous acid such as hydrochloric, hydrobromic or sulfuric acid to form the amino acid XVIII.
The amino acid XVIII may be protected using an amine protecting reagent such as di-t-butyldicarbonate (or other suitable reagents described in Theodora Greene, Peter Wuts xe2x80x9cProtective Groups in Organic Synthesistxe2x80x9d 2nd Ed. Wiley-Interscience, 1991) in water with an organic cosolvent such as t-butanol and a water soluble base such as sodium hydroxide or sodium bicarbonate to give the acid XIX.
The acid XIX is treated with amine VI (employing a molar ratio of XIX:VI within the range from about 1:1 to about 1:10) and a dehydrating agent such as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and or bromo-tris-pyrrolidinophosphonium hexafluorophosphate in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine in an inert solvent such as acetonitrile and/or dimethylformamide to form the amide XXI.
The amide XXI may be deprotected using the reagent appropriate for the protecting group used, for example, hydrogen chloride in an inert organic solvent such as dioxane, methanol or ethyl acetate for removal of the t-butyloxycarbonyl group, to form the amine XXII.
The amine XXII may be sulfonylated by reaction with a sulfonylating agent III (employing a molar ratio of XXII:III within the range from about 1:1 to about 1:10) in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine in an inert organic solvent such as acetonitrile, N,N-dimethylformamide, dichloromethane or dichloroethane to form compounds of the invention IE.
The starting nitrile II in General Scheme 5 can be prepared as described in the references cited in General Scheme 1. 
Referring to General Scheme 6, compounds of the invention IF may be prepared starting from the sulfonyl chloride XXIII which may be reacted with an amine VI (employing a molar ratio of XXIII:VI within the range from about 1:1 to about 1:10) in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine in an inert organic solvent such as acetonitrile, N,N-dimethylformamide, dichloromethane or dichloroethane to form compounds of the formula XXIV.
The sulfonamide XXIV may be epoxidized using an epoxidizing agent such as m-chloroperbenzoic acid or dimethyldioxirane in an inert organic solvent such as dichloromethane or acetone to form the epoxide XXV.
The epoxide XXV may be opened by reaction with concentrated aqueous ammonia either neat or with an organic cosolvent such as methanol or ethanol to form the aminoalcohol XXVI.
The aminoalcohol XXVI may be sulfonylated by reaction with a sulfonylating agent III (employing a molar ratio of XXVI:III within the range from about 1:1 to about 1:10) in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine in an inert organic solvent such as acetonitrile, N,N-dimethylformamide, dichloromethane or dichloroethane to form compounds of the invention IF.
An example of a sulfonyl chloride XXII in General Scheme 6 can be prepared as described in Ding, C Z. Synthetic Comm. 1996, 26, 4267-4273. 
Referring to General Scheme 7, compounds of the invention of formula IG may be prepared starting from bromide XXVII which may be metallated with t-butyllithium in an inert organic solvent such as tetrahydrofuran and the anion reacted with an acylating agent such as ethylchloroformate to form the ester XXVIII.
The ester XXVIII may react with epoxide forming reagents such as N-bromosuccinimide followed by base treatment, m-chloroperbenzoic acid, or dimethyldioxirane to form the epoxide XXIX.
The epoxide XXIX may be opened by reaction with concentrated aqueous ammonia either neat or with an organic cosolvent such as methanol or ethanol to form the aminoalcohol XXX.
The aminoalcohol XXX may be sulfonylated by reaction with a sulfonylating agent III (employing a molar ratio of XXXII:III within the range from about 1:1 to about 1:10) in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine in an inert organic solvent such as acetonitrile, N,N-dimethylformamide, dichloromethane or dichloroethane to form the sulfonamide XXXI.
The ester in compound XXXI may be hydrolyzed using a base such as potassium hydroxide, sodium hydroxide or lithium hydroxide in aqueous solution or in water with an organic cosolvent such as methanol, ethanol, ethylene glycol or dioxane to form the acid XXXII.
The acid XXXII may be treated with amine VI (employing a molar ratio of XIX:VI within the range from about 1:1 to about 1:10) and a dehydrating agent such as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide and or bromo-tris-pyrrolidinophosphonium hexafluorophosphate in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine in an inert solvent such as acetonitrile and/or dimethylformamide to form compounds of the invention IG.
An example of a bromide XXVII in General Scheme 7 where A and B are CH and D is N can be prepared as described in Barger, T. M.; Dulworth, J. K.; Kenny, M. T.; Massad, R.; Daniel, J. K.; Wilson, T.; Sargent, R. N.; J. Med. Chem., 1986, 29, 1590 and Evans, J. M.; Stemp, G.; Syn. Comm., 1988, 18, 1111. 
Referring to General Scheme 8, compounds of the invention IH may be prepared from the amine XXII by derivatization of the amine using an alkylating agent such as an alkyl halide or by reductive alkylation using an aldehyde and a suitable reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride or borane-pyridine complex in an organic solvent such as methanol, ethanol or acetic acid to form the amine compound XXXIII.
The amine compound XXXIII may be sulfonylated by reaction with a sulfonylating agent III (employing a molar ratio of XXXIII:III within the range from about 1:1 to about 1:10) in the presence of an organic base such as N,N-diisopropylethylamine or triethylamine in an inert organic solvent such as acetonitrile, N,N-dimethylformamide, dichloromethane or dichloroethane to form compounds of the invention IH.
Amine compounds XXII in General Scheme 8 have previously been described in General Scheme 5.
In the above Schemes, although the Q moiety is fixed at a definite position in the aromatic ring, it will be understood that the Q moiety may be attached at any appropriate position on the aromatic ring.
The compounds of formula I of the invention exhibit potassium channel inhibitory activity. They are blockers of the delayed rectifier voltage-gated potassium channel termed IKur which has been reported to contain the voltage gated potassium channel Kv 1.5 xcex1-subunit gene product. This gene product is believed to be important in the repolarization of the human atrial action potential. The compounds of the invention are useful in the treatment of cardiac arrhythmia especially those occurring in the atria as well as in cell proliferative disorders, such as leukemia and autoimmune diseases such as rheumatoid arthritis and transplant rejection.
Thus, compounds of formula I of the invention may be used as antiarrhythmic agents, i.e., for the prevention or treatment of arrhythmia including atrial arrhythmia. Thus, a composition containing one (or a combination) of the compounds of this invention, may be administered to a species of mammal (e.g., humans, dogs or cats) suffering from an arrhythmic condition.
A single dose, or two to four divided daily doses, provided on a basis of about 0.001 to about 100 mg per kilogram of body weight per day, preferably about 0.1 to about 25 mg per kilogram of body weight per day is appropriate. The substance is preferably administered orally, but parenteral routes such as the subcutaneous, intramuscular, intravenous or intraperitoneal routes or any other suitable delivery system, such as intranasal or transdermal routes can also be employed.
The compounds of this invention can also be formulated in combination with a cyclooxygenase inhibitor such as aspirin or indomethacin, a platelet aggregation inhibitor such as clopidogrel, ticlopidene or aspirin, fibrinogen antagonists or a diuretic such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorthiazide, trichloromethiazide, polythiazide or benzthiazide as well as ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamterene, amiloride and spironolactone and salts of such compounds, angiotensin converting enzyme inhibitors such as captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril, and salts of such compounds, angiotensin II antagonists such as losartan, irbesartan or valsartan, thrombolytic agents such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC, Eminase, Beecham Laboratories), or animal salivary gland plasminogen activators, calcium channel blocking agents such as verapamil, nifedipine or diltiazem, thromboxane receptor, antagonists such as ifetroban, prostacyclin mimetics, or phosphodiesterase inhibitors. Such combination products if formulated as a fixed dose employ the compounds of this invention within the dose range described above and the other pharmaceutically active agent within its approved dose range.
The compounds of formula I, and combinations thereof, can be formulated, as described above, in compositions such as tablets, capsules or elixirs for oral administration, in sterile solutions or suspensions for parenteral administration, and may also be administered via transdermal patch or nasal inhalation solutions. About 10 to about 500 milligrams of a compound of formula I is compounded with physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is such that a suitable dosage in the range indicated is obtained.